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Lay Summary: Use of stem cell therapies for Parkinson’s disease

The International Parkinson and Movement Disorder Society (MDS) has commissioned a brief review of the current place of cell-based therapies in Parkinson’s disease (PD) from recognized international experts of its Scientific Issues Committee. This review is intended to provide readers with a balanced view of the current state of cell therapies in PD.

The last few years have seen exciting advances in the development of potential new therapies for PD. Interest has focused in particular on cell based therapies, including the use of stem cells. Theoretically, such cells would be intended to replace or repair those lost or damaged in the disease process, thereby improving symptoms. However, there are important limitations to such a strategy. These include choosing and designing the right cells, turning them into nerve cells with normal physiological function, injecting them into the right place, making them connect to other remaining nerve cells and communicate with them without causing adverse side effects. Also, PD involves the loss of several different types of cell and to replace all or even some is a major challenge to cell therapy! All this must be achieved without side effects, including tumor formation – a particular potential risk with stem cells.

Several business enterprises in different countries world-wide offer ‘stem-cell therapies’ for many neurological diseases including Parkinson’s disease by injection of ‘stem-cells’ into the veins, the spinal fluid or even the brain. They use stem cells which may not be specifically engineered to replace or repair the functions of the degenerating neurons in Parkinson’s disease. Information about the outcome of these treatments would ideally be published in peer-reviewed medical and scientific journals. Unfortunately, such commercially-based treatments have failed to submit their techniques and results for independent scientific peer-review. Only one paper published by independent physicians reports no benefit for such patients. Despite this, many of these business enterprises make claims of considerable benefit that are unsubstantiated. This is a particularly serious issue given that the procedures involved have potentially very significant side effects.

The Society wishes to inform patients about some treatments are carried out without appropriate supportive scientific research and are performed outside a recognized academic or clinical setting. The Society fully supports research into the area of cell-based therapies and recognizes that there is much to be done in this important area. However, until such treatments are proven to be of benefit and published in recognized scientific journals that objectively scrutinize their procedures, the Society encourages patients to participate only in cell therapy studies that are part of a research program affiliated with a recognized academic institution.

Use of stem cell therapies for Parkinson's disease

Position paper of the International Parkinson and Movement Disorder Society

The last few years have seen exciting advances in the development of potential new therapies for Parkinson’s disease (PD). Interest has focused in particular on cell based therapies, including the use of stem cells. Theoretically such cells would be intended to replace or repair those lost in the disease process, thereby improving symptoms and signs. However, there are important limitations to such a strategy. These include choosing and designing the right cells, turning them into nerve cells, injecting them into the right place, making them connect to other remaining nerve cells and communicate with them. Also, PD involves the loss of several different types of cell and to replace all or even some is a major challenge to cell therapy! All this must be achieved without side effects, including tumour formation – a particular potential risk with stem cells.

At the request of the MDS President, the International Parkinson and Movement Disorder Society’s Scientific Issues Committee has commissioned a brief review of the current place of cell-based therapies in PD from recognized international experts. This review is intended to provide readers with a balanced view of the current state of cell therapies in PD.

The Society wishes to inform patients that some treatments are carried out without appropriate supportive scientific research and are performed outside a recognized academic or clinical setting. The Society fully supports research into the area of cell-based therapies and recognizes that there is much to be done in this important area. However, until such treatments are proven to be of benefit and published in recognized scientific journals, it would encourage patients only to participate in cell therapy studies that are part of a research program in a recognized centre of excellence.

Scientific Summary

The recent progress in stem cell technology and regenerative medicine has led to numerous attempts to use stem cell based therapies to repair the brain in patients with neurodegenerative disease.

Cellular therapy involves the introduction of new functional cells to restore damaged tissue. For example, in Parkinson’s disease (PD), one major approach has been the use of cellular therapy to supply a source of dopaminergic neurons to replace the function of those cells lost during the neurodegenerative process. Despite major advances in the field of regenerative medicine, several challenges to promote the use of stem cells for this type of therapy remain. Improvements in the supply of cells that can survive and differentiate into true nigral dopaminergic neurons and effectively re-innervate the dopamine deficient areas of the CNS are still required.

Furthermore, most approaches to cellular therapy overlook the widespread involvement of neuronal loss that occurs in PD, and so will only be as good as the current dopamine-based therapies but perhaps with some advantages if used in the right patient group and stage of disease. As a consequence, even if successful replacement of dopaminergic neurons is viable, such a practice would not represent a ‘cure’ as it would not address the treatment of dopamine-resistant motor features (such as freezing and postural instability) or the other non-motor features (such as dementia, hallucinations, olfactory loss or constipation) that are commonly seen in PD patients.

Therefore, while it is technically possible to differentiate stem cells that have properties similar to dopaminergic neurons, there is still considerable work yet to be done before this approach becomes feasible and useful in clinical practice. Research to improve and develop different avenues of cellular therapy for potential therapeutic application is currently underway. This includes work in transplanting fetal dopaminergic neurons, embryonic, mesenchymal and neural stem cells, and the use of reprogrammed fibroblasts.

Transplantation of Fetal dopaminergic neurons

Initial encouraging results from small, non-randomized studies to transplant fetal dopaminergic neurons demonstrated that successful re-innervation of the striatum could result in an improvement of motor function in patients with PD(1,2 3). However, when transplantation of embryonic dopaminergic neurons was performed in larger, randomized, sham-surgery controlled studies, no significant or only modest clinical benefits in patients with PD (aged 60 years or younger) were observed in the short term. Longer follow up studies were more encouraging(4, 5), especially in patients in whom preoperatively the dopaminergic denervation was restricted to the dorsal parts of the striatum6.

There is also no doubt that there is survival of the implanted dopamine neurons as this has been demonstrated by both post-mortem studies and functional PET studies in many patients 7, 8.

However, recent studies have demonstrated accumulation of inclusion bodies containing alpha-synuclein, ubiquitin and thioflavin-S in some of the transplanted dopaminergic neurons. There is evidence to suggest that alpha-synuclein can transfer between host and transplanted cells 9-12, indicating that implanted cells may acquire the same pathological processes that occur in PD. What this means for graft function is unknown, given that good long term graft effects have been seen and the number of cells displaying such pathology is small(5).

The post-surgical development of off-medication dyskinesias(13,14) in some patients undergoing fetal nigral transplantation has been of concern. These so called ‘graft induced dyskinesias’ (GIDs) are believed to be due to the heterogeneous extent of graft innervation across the striatum, as well as the ratio and numbers of surviving serotonergic and dopaminergic transplanted neurons5,15-6. In all cases where these GIDs have been disabling, they have responded to deep brain stimulation. Future advances to reduce GIDs may occur if the transplantation of graft-derived striatal serotonergic neurons could be minimized by selection and cell sorting- which may be easier with stem-cell derived neurons-or the use of serotonin 1A agonists. The current European TRANSNEURO study is designed to improve our understanding of the potential benefits of fetal cell implant therapy.

Stem cell therapy

Alternative sources of stem cells for transplantation are being investigated. An obvious advantage would be to provide greater numbers of dopaminergic neurons suitable for transplantation. Differentiation of dopaminergic neurons from bone marrow-derived mesenchymal stem cells, embryonic stem cells, neural stem cells or reprogrammed fibroblasts have all gained considerable interest at varying times, although the extent to which the derived cells are truly nigral dopaminergic neurons is often debatable.

Embryonic stem cells

Embryonic stem cells (eSCs) are pluripotent and thus can be differentiated into any type of cell in the body, including neurons with dopaminergic properties. Until recently, protocols for doing this were inefficient, although this has changed with a recently developed new protocol(17). Successful transplantation and survival of dopaminergic neurons differentiated from these eSCs has been performed in rodent models, with some evidence of functional recovery(17-21). Problems using this approach include the risk of tumours and teratoma formation(20, 22). The most recent approach avoids teratoma formation and overgrowth, and leads to the generation of better functional dopaminergic neurons. However much still needs to be done before these cells can be brought to the clinic.

Stem cells derived from bone marrow

Transplantation of bone marrow-derived stromal cells and mesenchymal stem cells (MSCs) differentiated into dopaminergic neurons has been reported to improve motor function in rodent models of PD, with no evidence of tumour formation(23), although whether the cells so derived are truly nigral dopaminergic neurons remains unproven. More experimental studies need to be done before these cells can be considered to be used in patients, although some, rather premature, clinical studies have already been undertaken without success.

Neural stem cells

Neural stem cells (NSCs) are a subtype of tissue-specific progenitor cells that are capable of extended self-renewal and have the potential to differentiate into all major sub-types of nervous tissue such as neurons, astroglia and oligodendroglia. Promising results have been reported in which differentiated non-human primate NSCs were transplanted into the non-human primate putamen and found to proliferate into fully functional dopaminergic neurons and improve function without causing graft-induced dyskinesias(24). In the case of human neural precursor cells, the best hope comes from using early ventral mesencephalic tissue and preferentially expanding up the early dopaminergic neuroblasts within it using selective growth factors(25). Some poorly described clinical studies using human NSCs isolated from cortical–subcortical brain tissues have been reported, although these studies are best regarded as being premature given that the scientific rationale underpinning them is poor.

Reprogrammed fibroblasts

One recent Nobel prize winning development in the field of stem cell biology is the discovery that adult cells can be reprogrammed to ‘rediscover’ their regenerative properties. This is achieved by increasing the expression of genes that allow the cell to become pluripotent and regain its original “stem-cell” properties. Originally this was done through the over -expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) which can re-program differentiated cells to become like embryonic stem cells(26). These cells are referred to as ‘induced pluripotential stem cells’ or iPS cells. iPS cells can be differentiated into dopaminergic neurons which could then be used for autologous transplantation in affected patients. Thus, this approach has fewer ethical problems compared to using fetal or ES cells and would also have a reduced risk of immunological rejection at the graft site. iPS cells derived from mice and transplanted into PD rat models have shown functional recovery in early studies(27). While dopaminergic neurons can now be generated from iPS cells, these cells still carry the risk of tumour formation similar to eSCs and differentiation rates are still too low to generate adequate numbers of dopaminergic neurons to be used in the clinical setting.

An even newer technology is the direct conversion of adult cells to dopaminergic neurons. Functional dopaminergic neurons generated directly from fibroblasts28-30 have recently been reported although functional improvement following grafting in animal models of disease is awaited.

Present publicly offered stem cell therapies for clinical use

There are several organizations world-wide which offer stem cell therapy for clinical application in patients. There is no detailed scientific information available on the outcome of these therapies. In a recent case series, data from patients with parkinsonism who underwent these procedures were collected retrospectively(31). The application of the procedure was neither recommended nor performed by the authors of this article. The report describes 17 patients with Parkinsonian syndromes who received intrathecal application of autologous unsorted bone marrow cells. There were no changes in motor function, activities of daily living, global clinical impression or antiparkinsonian medication after a median observation period of 10 months. Two patients (12%) reported a worsening of Parkinsonian symptoms, but the intervention was otherwise safe and well tolerated. Intrathecal application of autologous bone marrow cells in such uncontrolled conditions did not produce clinical benefit in these patients.

Summary

In order to provide good functional recovery to patients with PD, stem cell-based therapies need to be able to show that:

• the cells can differentiate into authentic NIGRAL dopaminergic neurons;
• they can survive and re-innervate the striatum;
• release dopamine in response to physiological stimuli;
• have functional benefits.

They should produce no adverse effects such as immune reactions, tumour formation or graft induced dyskinesias – although the latter are impossible to properly model in the laboratory which makes the translation of such cells to the clinic not straightforward. Prospective, double blinded clinical trials have failed to demonstrate a clear benefit of fetal dopaminergic cell transplants, but such a failure may relate as much to patient selection and trial design as to a failure of the cells to work per se. Furthermore, results from preclinical studies using differentiated dopaminergic neurons from other forms of stem cells whilst encouraging have so far failed to show extensive innervation of the striatum in ways that mimic fetal cells.

In summary, at the present time there is no evidence to support the use of stem cells in the treatment of PD. The future of cell-based therapies for PD requires an international approach through properly funded research and trials that should evolve in an iterative manner. At the moment the new trial being undertaken using fetal ventral mesencephalic tissue for PD in Europe may well represent the stepping-stone to future stem cell trials for PD.

The authors declare that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. RB is coordinator of the EU FP7 funded TRANSEURO project and is also a principle investigator on the EU funded projects NeuroStemCell and NeuroStemCellRepair

Disclosures unrelated to this work

Carolyn Sue has received grants from the Australian NHMRC, Australian Brain Foundation, PDNSW Association and has served on the advisory board for AbbVie.

Roger Barker has received grants from the MRC; NIHR; Parkinson's UK; Cure-PD; CHDI; EU; Rosetrees Trust the Michael J Fox Foundation. He also receives monies from Springer for editing the Journal of Neurology and book royalties from Wiley.

Jeffrey Kordower has financial interests in Ceregene, is an advisor for Brainstorm, n life, Medos and receives payment for being an editor of The Journal of Comparative Neurology

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The International Parkinson and Movement Disorder Society (MDS) is a professional society of over 6,500 clinicians, scientists and other healthcare professionals dedicated to improving the care of patients with movement disorders through education and research.